It is estimated that nearly 60 million Americans have at least one type of cardiac disease. One million of these people will die each year, many without the presentation of prior symptoms. In most cases these sudden cardiac deaths can be attributed to the physical rupture of atherosclerotic plaques, and the resulting myocardial infarct. Importantly though, only a subset of plaques are "vulnerable" or rupture prone. There is a major unmet medical need for new approaches for diagnosing, monitoring and treating vulnerable plaque. The long-term objective of this Programof Excellence in Nanotechnology (PEN) is to design nanodevices for the analysis, diagnosis, monitoring, and treatment of vulnerable atherosclerotic plaques. The PEN is a partnership between The Burnham Institute (lead), The Scripps Research Institute, and The University of California at Santa Barbara. The Specific Aims of the PEN are to: 1) Select for Targeting Elements that can be used to deliver nanodevices to vulnerable plaque. The Targeting Elements will be based upon homing peptides selected by in vivo phage display with animal models of atheroma, 2) Build Delivery Vehicles that can be used to transport drugs, imaging agents, and nanodevices to sites of vulnerable plaque, 3) Design a series of Self-Assembling Polymers that can be used as molecular nano-stents to physically stabilize vulnerable plaque, and to replace the fibrous cap with an anti-adhesive, anti-inflammatory surface, 4) Devise protein-driven Molecular Switches (MS) that can sense and respond to the pathophysiology of atheroma. The Molecular Switches will take advantage of the in-depth knowledge on the composition of atheroma and on its local environment, and 5) Devise Bio-nanoelectromechanical systems (BioNEMS) capable of sensing and responding to vulnerable plaque Ultimately the capability of these BioNEMS will be extended to incorporate diagnostic and therapeutic capability.